Advances in characterizing the neuropathology and functional dysconnectivity of depression and promising trials with emerging circuit-targeted and fast-onset therapeutics are providing unprecedented opportunities to gain deeper insight into the neurobiology of this devastating and pervasive disorder. Because of practical and ethical limitations to dissecting these mechanisms in humans, continued progress will critically depend on our ability to emulate aspects of depressive symptomatology and treatment response in nonhuman organisms. Although various experimental models are currently available, they often draw skepticism from both clinicians and basic research scientists. We review recent progress and highlight some of the best leads to diversify and improve discovery end points for preclinical depression research.